Roberts syndrome is also known as: Roberts-SC phocomelia syndrome; Pseudothalidomide syndrome; Roberts-SC (pseudothalidomide); SC-phocomelia syndrome; SC syndrome; Hypomelia-hypotrichosis-facial hemangioma syndrome; Appelt-Gerken-Lenz syndrome [1,3,15,23,30]. In all the above synonyms, SC represent the initials of the two affected families where was the syndrome described for the first time [3]. When initially described in 1974 by Herrmann, pseudo-thalidomide or SC syndrome were thought to be distinct entities. Nowadays they are known to be a phenotypic variation of the Roberts syndrome [3].

History

The syndrome was initially described by John Roberts in 1919 and later reviewed by Appelt [2,3,30], but already in 1672, François Bouchard reported an autopsy of an infant with tetraphocomelia, bilateral cleft lip, abnormal fingers, hydrocephalus, micrognathia, and cryptorchidism and consistent with a Roberts syndrome [7]. Furthermore an unlabelled specimen from the Virchow Museum dated to 1898, and exhibiting tetraphocomelia with bilaterally cleft lip, was also later designated as the “Roberts syndrome" [10].

Incidence

The true incidence of the Roberts syndrome is unknown [3].

Case report

The following images show an example of Roberts syndrome. The images represent a combination of two cases of the Roberts syndrome diagnosed in our department.

Images 1, 2: The images show flat fetal profile with micrognathia and retrognathia.

The diagnosis of the Roberts syndrome can be suspected when the following anomalies are observed (note that there is a wide range of severity of malformations among the affected individuals, including siblings [1,5,12]):

Growth retardation: ranging from mild to severe. Prenatal growth retardation is the most consistent finding in all affected fetuses. Mean birth length and weight is below the third percentile in most term and prematurely-born affected infants [1]. Postnatal growth retardation can be moderate to severe and correlates with the severity of the limb and craniofacial malformations [1,3,8,12,14,15,18,23].

Limb malformations: bilateral symmetric tetraphocomelia or hypomelia caused by symmetric mesomelic shortening and anterior-posterior axis involvement. The frequency and degree of involvement of long bones is, in decreasing order: radii, ulnae, and humeri in the upper limbs; fibulae, tibiae, and femurs in the lower limbs [1,3,6,8,12,14,15]. However, the limb reduction can be asymmetrical [5,23].

The degree of the limb abnormalities follows a cephalo-caudal pattern: the upper limbs are more severely affected than the lower ones, with several cases of only upper limbs malformations [1].

The hand malformations essentially affect the thumb (proximal positioning, aplasia or hypoplasia). The fifth finger is the next most affected digit with clinodactyly, hypoplasia, or agenesis. Other observed anomalies are: syndactyly, clinodactyly, brachydactyly and oligodactyly. Severe cases can have only three fingers and, rarely, only one finger [1,3].
Elbow or knee flexion contractures and clubfeet have also been reported [1,12,14,17,23,32].

Intellectual ability. Mental retardation is present in the majority of affected individuals. However, normal intellectual and social development have been reported [1,8].

These, usually marked anomalies, make the ultrasonographic detection of the Roberts syndrome relatively easily recognizable.

Cytogenetic fetures

The diagnosis of the Roberts syndrome relies on cytogenetic testing [1]. Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the following findings:

1. Characteristic chromosomal abnormality is premature centromere separation (PCS), which describes the prematurely separated centromeres during metaphase and separation of the heterochromatic regions, also termed heterochromatin repulsion (HR). These anomalies are found in most chromosomes [1,2,8,12,14,20,26,31]. These aspects are most prominently observed at certain regions in which the chromatin is composed of highly reiterated base sequences [11]. The observed abnormalities are interpreted as evidence for the presence of a genetically determined disturbance affecting the normal mechanisms for pairing and disjoining of sister chromatids [11].

2. Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers [1,3].

3. The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads [1,20,26].

4. Aneuploidy, micronucleation and multilobulated nuclei are also common findings in Roberts syndrome’s cell cultures [1,2,20].

Carrier status cannot be determined by cytogenetic analysis [1,25]. Carrier testing of at-risk relatives may be available from laboratories offering clinical confirmation of mutations identified in research labs if the mutations have been identified in the family [1]. There is no correlation between the phenotypical severity of the Roberts syndrome and the importance of the cytogenetical changes [25].
In front of suggesting anomalies, cytogenic analysis of fetal cells, obtained from chorionic villi sample, amniocentesis or cordocentesis is required to confirm the diagnosis prenatally. The presence of premature centromere separation makes the diagnosis. But a negative cytogenetic analysis does not exclude Roberts syndrome [27,28]. In those cases, a second analysis using a different type of fetal tissue is required [3].
Note: the cytogenetical anomalies observed in Roberts syndrome are different from premature sister chromatid separation (PSCS) described in Cornelia de Lange syndrome and from premature centromere division (PCD) associated with mosaic variegated aneuploidy syndrome that are differential diagnosises [1].

Molecular genetic

The gene ESCO2 is the main gene with documented Roberts syndrome-causing mutations. It is is located on 8p21.1 locus [1,33]. The protein produce by the ESCO2 gene is required for the establishment of sister chromatid cohesion during S phase [26]. Sequence analysis of the ESCO2 gene is available on a research basis only [1]. Furthermore, some others genes have been suspected for being responsible of Roberts syndrome [21]. To date, no other phenotypes have been associated with mutations in ESCO2 [1].
In April 2008, there were 26 known mutations of the ESCO2 gene [13].

Normal gene product. Translation of the mRNA results in a protein with two different domains, the C-terminal portion with acetyltransferase activity and the N-terminal end, which binds to chromatin [1].

Abnormal gene product. The abnormalities reported in the ESCO2 gene are predicted to lead to loss of function, truncation in the protein, or amino acid changes The cellular phenotype resulting from this missense mutation is equivalent to the one produced by nonsense and frameshift mutations, indicating that the Roberts syndrome molecular mechanism involves loss of acetyltransferase activity [13]. Alterations in ESCO2 function result in lack of cohesion at heterochromatic regions, which may lead to activation of the mitotic spindle checkpoint with the subsequent mitotic delay and the impaired cell proliferation observed in RBS cells [1,13].

Differential diagnosis

While some syndromes share some of the clinical features of Roberts syndrome (RBS), a physical examination and skeletal survey followed by the finding of cytogenetic abnormalities should allow for differentiation between individuals with RBS and those with conditions that are clinically similar [1].

1) In cases of mild manifestations, syndromes with associated preaxial reduction defects to be considered in the differential diagnosis include the following:

Baller-Gerold syndrome, characterized by [1]:

Autosomal recessive inheritance.

Coronal craniosynostosis with ocular proptosis and bulging forehead.

Radial ray defect, manifest as oligodactyly, aplasia or hypoplasia of the thumb and radius.

Abnormalities of the long bones of the extremities. Upper limb bones are affected in an order of frequency starting with the thumb, followed by the radius, the humerus, the ulna, and finally the fingers on the ulnar side of the hand. In extreme cases, the radius, ulna, and humerus are lacking; and the hand bud arises from the shoulders. Legs may be affected but less severely.

First introduced as a sedative agent, thalidomide was also used to treat morning sickness. It was withdrawn from the market in the 1960s because of reports of teratogenicity. Currently, thalidomide is used to treat various cancers and dermatologic, neurologic, and inflammatory diseases [1].

3) Disorders with similar but not the same cytogenetic findings include the following:

Ultrasound examination. Because of the often marked anomalies, the sonographic pre-natal diagnosis of the Roberts syndrome is easy and possible as soon as 12 weeks [1,20,24]. Confirmation of the suspected diagnosis necessits cytogenetic testing [1].

Cytogenetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by cytogenetic testing of fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks" gestation or chorionic villus sampling at approximately 11 to 12 weeks of gestation.

Molecular genetic testing. The molecular genetic testing for prenatal diagnosis of Roberts syndrome is not available in routine. However, prenatal testing may be available for families in which the disease-causing mutation has been identified [1].

Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified [1].

Genetic counseling

Mode of inheritance:

The rare Roberts syndrome (RBS) is inherited in an autosomal recessive manner with marked variability of phenotypic expression [1,4,3,5,8,13,14,19,23]. As all the genopathies, the Roberts syndrome could affect several members of a family or twins [16,19,29]. The sex-ratio is logically 1:1 [12].

Risk to family members:

Parents of a proband

The parents of an affected child are obligate heterozygotes (carriers of one mutant allele) [1]. As usual in autosomal recessive pathologies, heterozygotes individual also called carriers are asymptomatics [1].

Sibs of a proband

At conception, each sib of an affected fetus has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected (not a carrier) [1,3,4].

Offspring of a proband

Pregnancies in affected individuals are rare. However, two have been reported in 1986 [1]. The offspring of an individual with RBS are obligate heterozygotes (carriers) [1].

Other family members of a proband

Each sib of the proband"s parents is at a 50% risk of being a carrier [1].

Prognosis

The prognosis and survival depends on the severity of malformations [1]. So, mortality is high among the most severely affected infants, but mildly affected children are more likely to survive to adulthood. However, survival beyond the infancy is quite infrequent [1,3]. The cause of death has not been reported for most affected individuals [1]. When detected before viability, termination of pregnancy can be offered. After viability, standard obstetrical management is not altered [3].

Postnatal management

Evaluations following initial diagnosis [1]

Radiographic documentation of the craniofacial, limb, and hand anomalies.

Orofacial and limb malformation assessment to determine the need for management and plastic surgery.